Vasopressin is involved in some cases of congestive heart failure where peripheral resistance is increased. The hormone exerts its action through two well defined receptor subtypes: vascular V1a and renal epithelial V2 receptors. V1a receptor antagonists may decrease systemic vascular resistance, increase cardiac output and prevent vasopressin induced coronary vasoconstriction. Thus, in conditions with vasopressin induced increases in total peripheral resistance and altered local blood flow, V1a receptor antagonists may be therapeutically useful agents. V1a receptor antagonists may decrease blood pressure, induce hypotensive effects and thus be therapeutically useful in treatment of some types of hypertension.
Vasopressin-induced antidiuresis, mediated by renal epithelial V2 receptors, helps to maintain normal plasma osmolality, blood volume and blood pressure. Antidiuresis is regulated by the hypothalamic release of vasopressin (antidiuretic hormone) which binds to specific V2 receptors on renal collecting tubule cells. This binding stimulates adenyl cyclase and promotes the cAMP-mediated incorporation of water pores into the luminal surface of these cells. The blockade of vasopressin V2 receptors is useful in treating diseases characterized by excess renal reabsorption of free water. Vasopressin-induced antidiuresis, mediated by renal epithelial V2 receptors, helps to maintain normal plasma osmolality, blood volume and blood pressure. V2 antagonists may correct the fluid retention in congestive heart failure, liver cirrhosis, nephritic syndrome, central nervous system injuries, lung disease and hyponatremia.
Elevated vasopressin levels occur in congestive heart failure which is more common in older patients with chronic heart failure. In patients with hyponatremic congestive heart failure and elevated vasopressin levels, a V2 antagonist may be beneficial in promoting free water excretion by antagonizing the action of the antiduretic hormone. On the basis of biochemical and pharmacological effects of the hormone, antagonists of vasopressin are expected to be therapeutically useful in the treatment or prevention of state diseases involving vasopressin disorders in mammals, which include inducing vasodilation and aquaresis (free-water diuresis), treating hypertension, and inhibiting platelet aggregation. They are useful in the treatment of cardiac insufficiency, coronary vasospam, cardiac ischemia, renal vasospasm, cirrhosis with ascites, the syndrome of inappropriate anti-diuretic hormone secretion (SIADH), congestive heart failure, nephritic syndrome, brain edema, cerebral ischemia, cerebral hemorrhage-stroke, thrombosis bleeding, and abnormal states of water retention. Furthermore, vasopressin receptor antagonists have been found to be useful in treating disturbances or illnesses of the inner ear, particularly those related to Meniere's disease (Zenner et al., WO 99/2405-A2 (1999); and for the prevention and treatment of ocular circulatory disorders, particularly intraocular hypertension or glaucoma and vision disorders such as shortsightedness (Ogawa et al., WO 99/38533-A1 (1999)).
Vasopressin plays a vital role in the conservation of water by concentrating the urine at the site of the collecting ducts of the kidney. The collecting ducts of the kidney are relatively impermeable to water without the presence of vasopressin at the receptors and therefore, the hypotonic fluid formed after filtering through the glomeruli, passing the the proximal convoluted tubule, the loops of Henle, and the distal convoluted tubules, is excreted as dilute urine. However, during dehydration, volume depletion or blood loss, vasopressin is released from the brain and activates the vasopressin V2 receptors in the collecting ducts of the kidney rendering the ducts permeable to water; hence water is reabsorbed and a concentrated urine is excreted. In patients and animals with central or neurogenic diabetes insipidus, the synthesis of vasopressin in the brain is defective and therefore, they produce no or very little vasopressin, but their vasopressin receptors in the kidneys are normal. Because they cannot concentrate the urine, they may produce as much as ten times the urine volumes of their healthy counterparts and they are very sensitive to the action of vasopressin and vasopressin V2 agonists. Vasopressin and desmopressin, which is a peptide analog of the natural vasopressin, are being used in patients with central diabetes insipidus. Vasopressin V2 agonists are also useful for the treatment of nocturnal enuresis, nocturia, urinary incontinence and temporary delay of urination whenever desirable.
Premature labor remains the leading cause of perinatal mortality and morbidity. Infant mortality dramatically decreases with increased gestational age. While many agents have been developed for the treatment of premature labor in the last 40 years, the incidence of pre-term births and low birth weight infants has remained relatively unchanged. Therefore, there is an unmet need for safer and more efficacious agents for the treatment of preterm labor with better patient tolerability. Currently available agents (terbutaline, albuterol), magnesium sulfate, NSAIDs (indomethacin), and calcium channel blockers are not very effective and their safety profile is not ideal. One target of interest is the oxytocin receptor and a selective oxytocin receptor antagonist has been proposed as an ideal tocolytic agent. There is evidence strongly suggesting that oxytocin may play a critical role in the initiation and progression of labor in humans (Fuchs et al. Science 215, 1396–1398 (1982); Maggi et al. J. Clin. Endocrinol. Metab. 70, 1142–1154 (1990); Åkerlund, Reg. Pept. 45, 187–191 (1993); Åkerlund, Int. Congr. Symp. Semin. Ser., Progress in Endocrinology 3, 657–660 (1993); Åkerlund et al., in Oxytocin, Ed. R. Ivell and J. Russel, Plenum Press, New York, pp 595–600 (1995)). Thus, a selective oxytocin antagonist is expected to block the major effects of oxytocin exerted mainly on the uterus at term, and to be more efficacious than current therapies for the treatment of preterm labor. By virtue of its direct action on the receptors in the uterus an oxytocin antagonist is also expected have fewer side effects and an improved safety profile.
Oxytocin antagonists can produce contraception in mammals by inhibiting the release of oxytocin-stimulated luteneizing hormone (LH) from pituitary cells (Rettori et al., Proc. Nat. Acad. Sci. U.S.A. 94, 2741–2744 (1997); Evans et al., J. Endocrinol., 122, 107–116 (1989); Robinson et al., J. Endocrinol. 125, 425–432 (1990)).
The administration of oxytocin receptor antagonists to farm animals after fertilization have been found to enhance fertility rates by blocking oxytocin induced luteolysis leading to embryonic loss (Hickey et al., WO 96/09824 A1 (1996), Sparks et al., WO 97/25992 A1 (1997); Sparks et al., U.S. Pat. No. 5,726,172 A (1998)). Thus, oxytocin receptor antagonists can be useful in farm animal husbandry to control timing of parturition and delivery of newborns resulting in enhanced survival rates. They can be also useful for the synchronization of estrus by preventing oxytocin induced corpus luteum regression and by delaying estrus (Okano, J. Reprod. Dev. 42 (Suppl.), 67–70 (1996)). Furthermore oxytocin receptor antagonists have been found to have a powerful effect in inhibiting oxytocin-induced milk ejection in dairy cows (Wellnitz et al., Journal of Dairy Research 66, 1–8 (1999)).
Oxytocin is also synthesized in the brain and released in the central nervous system. Recent studies have established the importance of central oxytocin in cognitive, affiliative, sexual and reproductive behavior, and in regulating feeding, grooming and responses to stress in animals. Oxytocin may also influence normal behavior in humans. Modulators of oxytocin binding to its receptors in the central nervous system may be useful in the prevention and treatment of disfunctions of the oxytocin system, including obsessive compulsive disorder (OCD) and other neuropsychiatric disorders (Lovacs et al., Psychoneuroendocrinology 23, 945–962 (1998); McCarthy et al., U.K. Mol. Med. Today 3, 269–275 (1997); Bohus, Peptidergic Neuron [Int. Symp. Neurosecretion], 12th (1996), 267–277, Publ, Birkhauser, Basel, Switz.; Leckman et al., Psychoneuroendocrinology 19, 723–749 (1994).
Oxytocin antagonists also showing antagonist activity at the vasopressin V1a receptors have the ability to block uterine contractions induced by oxytocin and vasopressin. Thus, these compounds can be useful in the treatment of dysmenorrhea, a condition characterized by pain during menstruation. Primary dysmenorrhea is associated with ovulatory cycles, and it is the most common complain of gynecologic patients. Myometrial hypercontractility and decreased blood flow to the uterus are thought to be causative factors for the symptoms of primary dismenorrhea (Åkerlund, Acta Obstet. Gynecol. Scand. 66, 459–461 (1987)). In particular, vasoconstriction of small uterine arteries by vasopressin and oxytocin is thought to produce tissue ischemia and pain (Jovanovic et al., Br. J. Pharmacol., 12, 1468–1474 (1997); Chen et al., Eur. J. Pharmacol., 376, 25–51 (1999)).
The following prior art references describe peptidic vasopressin antagonists: Manning et al. J. Med. Chem., 35, 382 (1992); Manning et al, J. Med. Chem., 35, 3895 (1992); Gavras et al., U.S. Pat. No. 5,070,187 (1991); Manning et al., U.S. Pat. No. 5,055,448 (1991); Ali, U.S. Pat. No. 4,766,108 (1988); Ruffolo et al., Drug News and Perspectives, 4(4), 217 (1991).
The following prior art references describe peptidic oxytocin antagonists: Hruby et al., Structure-Activity Relationships of Neurohypophyseal Peptides, in The Peptides: Analysis, Synthesis and Biology, Udenfriend and Meienhofer Eds., Academic Press, New York, Vol. 8, 77–207 (1987); Pettibone et al., Endocrinology, 125, 217 (1989); Manning et al., Synthesis and Some Uses of Receptor-Specific Agonists and Antagonists of Vasopressin and Oxytocin, J. Recept. Res., 13, 195–214 (1993); Goodwin et al., Dose Ranging Study of the Oxytocin Antagonist Atosiban in the Treatment of Preterm Labor, Obsetet. Gynecol., 88, 331–336 (1996). Peptidic oxytocin antagonists suffer from a lack of oral activity and many of these peptides are non-selective antagonists since they also exhibit vasopressin antagonist activity. Bock et al. [J. Med. Chem. 33, 2321 (1990)], Pettibone et al. [J. Pharm. Exp. Ther. 256, 304 (1991)], and Williams et al. [J. Med. Chem., 35, 3905 (1992)] have reported on potent hexapeptide oxytocin antagonists which also exhibit weak vasopressin antagonistic activity in binding to V1 and V2 receptors.
Various non-peptidic oxytocin antagonists and/or oxytocin/vasopressin (AVP) antagonists have recently been reported by Pettibone et al., Endocrinology, 125, 217 (1989); Yamamura et al., Science, 252, 572–574 (1991); Yamamura et al., Br. J. Pharmacol., 105, 787 (1992); Evans et al., J. Med. Chem., 35, 3919–3927 (1992); Pettibone et al., J. Pharmacol. Exp. Ther, 264, 308–314 (1992); Ohnishi et al., J. Clin. Pharmacol. 33, 230–238, (1993); Evans et al., J. Med. Chem. 36, 3993–4006 (1993); Pettibone et al., Drug Dev. Res. 30, 129–142 (1993); Freidinger et al., General Strategies in Peptidomimetic Design: Applications to Oxytocin Antagonists, in Perspect. Med. Chem. 179–193 (1993), Ed. B. Testa, Verlag, Basel, Switzerland; Serradeil-LeGal, J. Clin. Invest, 92, 224–231 (1993); Williams et al., J. Med. Chem. 37, 565–571 (1994); Williams et al., Bioorg. Med. Chem. 2, 971–985 (1994); Yamamura et al., Br. J. Pharmacol., 105, 546–551 (1995); Pettibone et al., Advances in Experimental Medicine and Biology 395, 601–612 (1995); Williams et al., J. Med. Chem. 38, 4634–4636 (1995); Hobbs et al., Biorg. Med. Chem. Lett. 5, 119 (1995); Williams et al., Curr. Pharm. Des. 2, 41–58 (1996); Freidinger et al., Medicinal Research Reviews, 17, 1–16 (1997); Pettibone et al., Biochem. Soc. Trans. 25 (3), 1051–1057 (1997); Bell et al., J. Med. Chem. 41, 2146–2163 (1998); Kuo et al., Bioorg. Med. Chem. Lett. 8, 3081–3086 (1998); Williams et al., Biorg. Med. Chem. Lett. 9, 1311–1316 (1999).
Non-peptidic vasopressin antagonists have recently been disclosed, Albright et al. U.S. Pat. No. 5,536,718-A, U.S. Pat. No. 5,532,235-A, U.S. Pat. No. 5,516,774-A, U.S. Pat. No. 5,512,563-A, U.S. Pat. No. 5,459,131-A; Venkatesan et al. U.S. Pat. No. 5,521,173-A; Ogawa et al., EP 0514667-A1, EPO 382185-A2, WO 91/05549 and U.S. Pat. No. 5,258,510, WO 94/04525; Yamanouchi Pharm. Co. Ltd. WO 94/20473, WO 94/12476, WO94/14796; Fujisawa Co, Ltd. EP 620216-A1; Ogawa et al. EP470514A; Bock et al. EP 0533242-A and EP 0533244-A; Erb et al. EP 0533240-A; Gilbert et al. EP 0533243 A. Certain carbostyril derivatives and bicyclic azepines are disclosed as oxytocin and vasopressin antagonists by Ogawa et al. in WO 94/01113 (1994); benzoheterocyclic derivatives as vasopressin and oxytocin antagonists are disclosed by Ogawa et al. in WO 95/34540-A (1995); benzazepine derivatives with anti-vasopressin activity, oxytocin antagonistic activity and vasopressin agonist activity, useful as vasopressin antagonists, vasopressin agonists and oxytocin antagonists are disclosed by Ogawa et al. in WO 97/22591 (1997) and U.S. Pat. No. 6,096,736 (2000); benzoxazinones are disclosed as oxytocin and vasopressin receptor antagonists by Sparks et al. in WO 97/25992 (1997); Williams et al. disclose piperidine oxytocin and vasopressin receptor antagonists in WO 96/22775 (1996); Bock et al. disclose benzoxazinone and benzopyrimidinone piperidines useful as oxytocin and vasopressin receptor antagonists in U.S. Pat. No. 5,665,719 (1997); piperazines and spiropiperidines useful as oxytocin and vasopressin receptor antagonists are disclosed by Evans et al. in U.S. Pat. No. 5,670,509 (1997) and by Bock et al. in U.S. Pat. No. 5,756,504 (1998); Bell et al. disclose piperazine oxytocin receptor antagonists in UK Patent Application, GB 2 326 639 A (1998); Bell et al. disclose benzoxazinone and quinolinone oxytocin and vasopressin receptor antagonists in UK Patent Application GB 2 326 410 A (1998); Bell et al. disclose benzoxazinone oxytocin and vasopressin receptor antagonists in U.S. Pat. No. 5,756,497 (1998); Matsuhisa et al. disclose difluoro tetrahydrobenzazepine derivatives as oxytocin antagonists in WO 98/39325 (1998); and Ogawa et al. disclose heterocyclic bisamides with vasopressin and oxytocin antagonist activity in U.S. Pat. No. 5,753,644 (1998). Ohtake et al. disclose ocular tension lowering agents and phosphoric ester derivatives exhibiting vasopressin V1 receptor antagonism in WO 99/65525 (1999); and Hoekstra et al. disclose tricyclic benzodiazepines useful as vasopressin receptor antagonists for treating conditions involving increased vascular resistance and cardiac insufficiency in WO 00/43398 (2000).
Trybulski et al. disclose 3-carboxamide derivatives of pyrrolobenzodiazepine bisamides with vasopressin antagonist activity in U.S. Pat. No. 5,880,122 (1999); bicyclic thienoazepines with vasopressin and oxytocin receptor antagonist activity are disclosed by Albright et al. in WO 96/22294 (1996) and U.S. Pat. No. 5,654,297 (1997); and tricyclic benzazepines with vasopressin and oxytocin receptor antagonist activity are disclosed by Albright et al. in U.S. Pat. No. 5,849,735 (1998); and Venkatesan et al. in U.S. Pat. No. 5,436,333 teach a process for the preparation of tricyclic heterocycles which are useful as intermediates in the production of cardiovascular agents.
Venkatesan et al. broadly disclose tricyclic benzazepines with vasopressin and oxytocin antagonist activity in U.S. Pat. No. 5,521,173 (1996), WO 96/22292 (1996), and in U.S. Pat. No. 5,780,471 (1998).
Albright et al. broadly disclose tricyclic benzazepine vasopressin antagonists in WO 96/22282A1 (1996) which possess antagonistic activity at the V1 and/or V2 receptors and exhibit in vivo vasopressin antagonistic activity, as well as antagonistic activity at the oxytocin receptors.